Antiviral protein protects against COVID-19 in live mouse models

A mammalian protein that UT Southwestern microbiologists previously showed to inhibit the virus that causes COVID-19 in cell culture also protected live mouse models, significantly limiting infection in lung cells and decreasing symptoms. The findings, published in microbiology of natureit could lead to new strategies to treat COVID-19, which still infects thousands and kills hundreds in the US every week.

“Our 2020 paper showed that LY6E could inhibit SARS-CoV-2 in cultured cells. But the test shows that it has the same role in living models,” said study lead author John Schoggins, Ph.D., Professor Microbiology Associate. in southwestern UT. “We have shown for the first time that the natural antiviral protein LY6E reduces disease from COVID-19 in a living model.”

Human bodies use a variety of strategies to fight viral infections, including the production of antiviral proteins, which are the focus of Schoggins’ lab. In 2020, he and his colleagues discovered that one of these proteins, LY6E, blocked infection in cell cultures against a variety of coronavirusincluding one specific to mice called mouse hepatitis virus (MHV), as well as the viruses responsible for the severe acute respiratory syndrome (SARS) outbreak in 2003 and the Middle East respiratory syndrome (MERS) outbreak in 2012. But how LY6E protects against coronavirus infection and whether it could perform the same feat in animal models of COVID-19 was unknown.

To answer these questions, Dr. Schoggins and his colleagues used a genetic technique to generate seven live mouse models, each designed to turn off LY6E in specific immune cells, in all immune cells, or in the whole body. Mice lacking this protein in their entire bodies or in all their immune cells usually died of MHV infection. The mouse models also became more vulnerable when the gene was turned off only in immune cells (B cells or monocytes), demonstrating the importance of LY6E in these cells in fighting coronavirus infections.

Mouse models without LY6E but infected with SARS-CoV-2 developed moderate symptoms including weight loss and inflammation and bleeding in the lungs, all signs of disease not seen in models with typical LY6E levels.

A genetic analysis of the lungs showed that the epithelial cells had significant changes in gene expression. A closer look showed that two subsets of these cells, called club cells and hair cells, appeared to be most affected by infection in models without LY6E. The findings suggest that LY6E produced by these types of lung epithelial cells is critical in limiting SARS-CoV-2 infection, said Dr. Schoggins, a Nancy Cain and Jeffrey A. Marcus Medical Research Fellow, honoring Dr. Bill S. Vowell. .

In the future, he added, researchers could develop treatments for COVID-19 that rely on delivering additional LY6E-producing genes or mimicking their action with a drug. Furthermore, mice lacking LY6E could be used as more realistic models for SARS-CoV-2 infection to study drugs or vaccines. Instead of developing a fatal infection like most existing animal models of COVID-19 with other genetic alterations, or without symptoms like normally functioning LY6E mice do, mice lacking LY6E develop a COVID-like illness. -19 Mild to moderate, which more closely mimics most cases of the disease in humans.

Postdoctoral researcher Katrina Mar, Ph.D., now of the Memorial Sloan Kettering Cancer Center and Institute, led the study. Other contributing UTSW researchers included Alexandra I. Wells, Ph.D., Postdoctoral Researcher; Marley C. Caballero Van Dyke, Ph.D., research scientist; Jennifer L. Eitson, senior research associate; Natasha W. Hanners, MD, Assistant Professor of Pediatrics; Bret M. Evers, MD, Ph.D., Assistant Professor of Pathology and Ophthalmology; and John M. Shelton, laboratory director.